Sirolimus interacts with pathways essential for podocyte integrity.
BACKGROUND
The specific mTor inhibitor sirolimus has been implicated in the pathogenesis of renal glomerular lesions and nephrotic syndrome appearance after transplantation. Podocyte injury and focal segmental glomerulosclerosis have been related to sirolimus therapy in some patients but the pathways underlying these lesions remain hypothetical.


METHODS
To go further in the comprehension of these mechanisms, primary cultures of human podocytes were exposed to therapeutic-range concentrations of sirolimus.


RESULTS
Cell viability was not affected after 2 days' exposure to the drug but changes in cell phenotype and cytoskeleton reorganization were observed. We also evidenced that vascular endothelial growth factor (VEGF) synthesis and Akt phosphorylation were decreased by sirolimus addition. We did not observe any loss of podocyte differentiation markers with the notable exception of WT1, a transcription factor essential for maintaining podocyte integrity. WT1 gene and protein expression in podocytes were decreased in a dose-dependent manner after incubation with sirolimus.


CONCLUSIONS
Taken together, these data suggest that sirolimus could impair pathways essential for podocyte integrity and therefore predisposes to glomerular injury.
Letavernier
Emmanuel
E
INSERM, U702 and Université Pierre et Marie Curie-Paris 6, UMRS702, Paris, France. emmanuel.letavernier@tnn.ap-hop-paris.fr
Bruneval
Patrick
P
Vandermeersch
Sophie
S
Perez
Joelle
J
Mandet
Chantal
C
Belair
Marie-France
MF
Haymann
Jean-philippe
JP
Legendre
Christophe
C
Baud
Laurent
L
D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D016162:Genes, Wilms Tumor / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008954:Models, Biological; D010641:Phenotype; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D025721:WT1 Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus